The assessment and therapy of autoimmune diseases are poorly studied. This is in part due to the rarity and heterogeneity of many of these disorders as well as the uncertainty of their pathogeneses. One aim of this project is to standardize the conduct and reporting of clinical studies of autoimmune diseases and to coordinate international efforts in this area in order to develop improved therapies. Also, as more environmental risk factors for disease onset or disease exacerbation are identified, the possibility of conducting clinical trials of preventative therapies becomes more feasible. The standardization of outcomes and clinical trial designs are critical to optimize the efficiency and success of such therapeutic and preventative strategies. [unreadable] [unreadable] For this project, we are now focusing on the idiopathic inflammatory myopathies (IIM), also known as the myositis syndromes, as prototypic autoimmune diseases from which principles learned in these disorders may be applied generally to other diseases. The IIM are associated with substantial lifelong morbidity and mortality. Their treatment is unsatisfactory in many cases and drug efficacy evaluation is hampered by the lack of reliable and standardized measures of disease outcome. No agents are currently licensed for the treatment of IIM and few have been studied in randomized controlled clinical trials. [unreadable] [unreadable] Because of the lack of consensus on how to best measure disease in the myositis syndromes, and to enhance recruitment of patients for other studies, new disease assessment tools are being developed and validated to apply to all forms of myositis in both adults and children. We have organized a collaborative group of over 100 adult and pediatric specialists with special interest in myositis, known as the International Myositis Assessment and Clinical Studies Group (IMACS) to assist in this project. The goals of IMACS are to standardize the conduct and reporting of clinical studies in all forms of IIM. Achieving these goals should enhance the consistency by which clinical trials are performed, improve the capacity to compare different treatments, and encourage development of promising novel therapeutic agents. Therapeutic studies of novel biologic agents are in progress and others are being planned to utilize these outcome measures in prospective trials.[unreadable] [unreadable] Together, and with input from the FDA, IMACS has: 1) developed and validated new tools to assess myositis disease activity and damage; 2) achieved consensus on core set outcome measures to comprehensively describe disease activity; 3) delineated preliminary definitions of improvement for use as clinical trial outcomes, which provide clinically meaningful change in combinations of the core set measures in a composite endpoint; and 4) developed international consensus guidelines on details of the conduct of multi-center therapeutic trials for adult and juvenile IIM. We have created a website to consolidate all IMACS activities, including member lists and contacts, educational materials, meeting presentations, references, assessment tools and ongoing and future collaborative initiatives and studies (https://dir-apps.niehs.nih.gov/imacs/).[unreadable] [unreadable] The therapy of the IIM is focused on immunosuppression to minimize effects from immune activation and rehabilitation to improve remaining muscle function. Given the poor outcomes of myositis patients with standard therapy, novel biologic anti-inflammatory agents, which have been shown to be safe and effective for other immune-mediated diseases and have rationale for use in myositis, are reasonable candidates for study and may represent important advances in the treatment of IIM in the future. Our experience is that conducting therapeutic trials also greatly enhances recruitment to our epidemiologic investigations. [unreadable] [unreadable] Infliximab is one of several anti-TNF alpha agents shown to be safe and effective for a number of immune-mediated diseases. It is a chimeric IgG1 kappa monoclonal antibody that neutralizes TNF by binding with high affinity to the soluble and transmembrane forms of TNF and inhibits binding of TNF with its receptors. In collaboration with Paul Plotz, we have initiated a Phase 1-2 randomized, double-blind, placebo-controlled trial of infliximab in 28 patients with PM and DM. The goals of this study are to: 1) assess the safety and efficacy of intravenous infliximab in refractory patients receiving corticosteroids and another immunosuppressive agent; 2) determine the effective dose of infliximab in the therapy of PM/DM patients; and 3) perform gene expression profiling in muscle before and after therapy to help define pathophysiological cascades involved in the progression of these diseases and molecular signatures of responses to anti-TNF therapy. Refractory patients are randomly assigned to receive either 3 mg/kg body weight of infliximab or a placebo. Four infusions are given prior to week 16, the primary outcome assessment time point, when muscle strength and other IMACS core outcome measures are assessed. Patients who improve with treatment will continue with the same dose for four additional infusions. Those who do not improve will be randomized to receive either 5 mg/kg or 10/mg/kg of infliximab for four more infusions. Outcome assessments will be performed at weeks 0, 6, 16 and 40. [unreadable] [unreadable] Additional therapeutic studies are under consideration including a novel placebo phase design investigation of rituximab, an anti-CD20 monoclonal antibody that has been recently approved for rheumatoid arthritis and has shown evidence of efficacy in many other autoimmune diseases.[unreadable] [unreadable] There is a lack of validated biomarkers for disease activity and damage in many autoimmune diseases. To address this need, we are assessing the usefulness of novel biomarkers of muscle inflammation and damage in IIM in a variety of studies. One approach has been measuring muscle metabolites (Creatine (Cr), choline (Cho), betaine (Bet), glycine (Gly), trimethylamine oxide (TMAO)) by 1H magnetic resonance spectroscopy in first morning void urine and correlating them with age-adjusted creatinine (Cn) ratios. We found that urinary Cr:Cn, Cho:Cn, Bet:Cn, Gly:Cn, and TMAO:Cn ratios are elevated in juvenile IIM and that Cr:Cn correlates strongly with global disease damage. Thus, the assessment of the urinary Cr:Cn ratio may have great utility as a non-invasive marker of myositis disease damage.[unreadable] [unreadable] The identification of environmental risk factors for autoimmune diseases offers the hope of preventing some of these disorders by exposure avoidance in genetically susceptible individuals. Investigations underway in our companion study - ES101074 DIR, Environmental/genetic Risk Factors and Pathogenesis of Autoimmune Disease ? are focused on identifying environmental risk factors for autoimmune conditions and may offer such approaches to disease prevention. Exposures that are known to be important in inducing disease exacerbations in established disease may be triggers for disease onset as well. On example is our recent finding that ultraviolet radiation, known to induce exacerbations of lupus and dermatomyositis, likely plays an important role in the development of dermatomyositis and related autoantibodies. Studies to assess the efficacy of ultraviolet radiation avoidance in reducing dermatomyositis disease flares are now under consideration.